The extracellular matrix (ECM) within native tissues consists predominantly of cross-linked elastin and collagen that contribute to the biologic and mechanical properties of the tissue. Various factors can compromise tissue homeostasis including congenital absence or degradation of elastin and malformation of elastin as well as limited elastin regeneration following damage caused by, e.g., disease or surgical procedures, due to innately poor elastin synthesis by adult vascular cells.
Elastin is a key component of the ECM that allows the matrix to stretch and retract following mechanical loading and release. Vascular smooth muscle cells (SMCs) typically synthesize elastin as a soluble tropoelastin, which is then post-translationally cross-linked by lysyl oxidase to form an insoluble matrix. In addition to providing structural support and suppleness to the tissue, elastin is also critical in regulating SMC behavior, especially during vascular morphogenesis and disease. Thus, mechanical disruption of the vascular elastin matrix, e.g., progressive damage due to conditions such as atherosclerosis or aneurysm, the congenital absence of elastin or deformation of the elastin matrix, for instance due to surgical procedures such as angioplasty, can severely compromise vascular homeostasis.
One of the aims of current research in tissue engineering is to generate, both in vivo and ex vivo, for instance as graft materials, functional blood vessels and cardiac tissue (e.g., heart valve tissue). The attainment of this goal requires the ability to create structurally and functionally-faithful vascular elastic matrices. Unfortunately, many challenges related to adequate mechanical strength and long-term functionality still remain to be solved. One of the reasons for limited progress to date is the unavailability of materials, e.g., cues, that can up-regulate innately poor elastin synthesis by adult vascular cells. Another problem that must be overcome is the tendency of vascular cells to become hyper-prolific during inflammatory vascular disease, which often accompanies the disease states that compromise tissue homeostasis due to lack of a healthy elastin network in the tissue.
Previous studies have suggested that use of hyaluronan (HA) based matrices in smooth muscle cell (SMC) development may improve elastin synthesis, maturation, and stabilization (Ramamurthi, et al., Biomaterials 26 (2005) 999-1010). Further research into the possible use of HA in vascular tissue engineering applications has shown that UV surface modification of HA-based matrices does not significantly alter inherently poor platelet binding characteristics of HA gels, nor do the treated matrices show any increase in thrombogenic characteristics (Amarnath, et al., Biomaterials 27 (2006) 1416-1424). However, when the HA matrices were examined for elastogenic effects, long-chain HA (MW>1×106 Da), and large fragments (MW>2×104 Da) either had little or no effect or even significantly inhibited total and crosslinked elastin matrix synthesis (Joddar, et al., Biomaterials 27 (2006) 2994-3004, FIG. 1).
What are needed in the art are materials that can be utilized in tissue engineering applications to encourage the development of functional and structurally sound connective tissues (e.g., cardiovascular tissues) characterized by a well-developed elastin matrix structure.